Abstract
Recent advances in molecular electrophysiology have made possible
the development of more selective ion channel blockers for therapeutic
use. However, more information is needed about the effects of blocking
specific channels on repolarization in normal human atrium and in
atrial cells of patients with atrial fibrillation (AF). AF-induced
electrical remodeling is associated with reductions in transient
outward current (Ito), ultrarapid delayed rectifier current (IKur),
and L-type calcium current (ICa,L). Direct evaluation of the results
of ion channel depression is limited by the nonspecificity of the
available pharmacological probes. OBJECTIVES: Using a mathematical
model of the human atrial action potential (AP), we aimed to: (1)
evaluate the role of ionic abnormalities in producing AP changes
characteristic of AF in humans and (2) explore the effects of specific
channel blockade on the normal and AF-modified AP (AFAP). METHODS:
We used our previously developed mathematical model of the normal
human atrial AP (NAP) based on directly measured currents. We constructed
a model of the AFAP by incorporating experimentally-measured reductions
in Ito (50\%), IKur (50\%), and ICa,L (70\%) current densities observed
in AF. RESULTS: The AFAP exhibits the reductions in AP duration (APD)
and rate-adaption typical of AF. The reduction in ICa,L alone can
account for most of the morphological features of the AFAP. Inhibition
of Ito by 90\% leads to a reduction in APD measured at -60 mV in
both the NAP and AFAP. Inhibition of the rapid component of the delayed
rectifier (IKr) by 90\% slows terminal repolarization of the NAP
and AFAP and increases APD by 38\% and 34\%, respectively. Inhibition
of IKur by 90\% slows early repolarization and increases plateau
height, activating additional IK and causing no net change in APD
at 1 Hz in the NAP. In the presence of AF-induced ionic modifications,
IKur inhibition increases APD by 12\%. Combining IKur and IKr inhibition
under both normal and AF conditions synergistically increases APD.
In the NAP, altering the model parameters to reproduce other typical
measured AP morphologies can significantly alter the response to
K$^+$-channel inhibition. CONCLUSIONS: (1) The described abnormalities
in Ito, IKur and ICa,L in AF patients can account for the effects
of AF on human AP properties; (2) AP prolongation by IKur block is
limited by increases in plateau height that activate more IK; (3)
Blockers of IKur may be more effective in prolonging APD in patients
with AF; 4) Inhibition of both IKur and IKr produces supra-additive
effects on APD. These observations illustrate the importance of secondary
current alterations in the response of the AP to single channel blockade,
and have potentially important implications for the development of
improved antiarrhythmic drug therapy for AF.
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